PROCESS FOR PREPARING 3,5-BIS(HALOALKYL)PYRAZOLE DERIVATIVES FROM a,a-DIHALOAMINES

ABSTRACT

The present invention relates to a novel process for preparing 3,5-bis(haloalkyl)pyrazole derivatives.

The present invention relates to a novel process for preparing3,5-bis(haloalkyl)pyrazole, especially 3,5-bis(fluoroalkyl)pyrazolederivatives.

Polyhaloalkylpyrazolylcarboxylic acid derivatives, especiallypolyfluoroalkylpyrazolylcarboxylic acid derivatives and3,5-bis(fluoroalkyl)pyrazoles are valuable precursors of activefungicidal ingredients (cf. WO 2003/070705 and WO 2008/013925).

Pyrazolecarboxylic acid derivatives are typically prepared by reactingacrylic acid derivatives having two leaving groups with hydrazines (cf.WO 2009/112157 and WO 2009/106230). WO 2005/042468 discloses a processfor preparing 2-dihaloacyl-3-aminoacrylic esters by reacting acidhalides with dialkylaminoacrylic esters and subsequent cyclizationthereof with alkyl hydrazines. WO 2008/022777 describes a process forpreparing 3-dihalomethylpyrazole-4-carboxylic acid derivatives byreacting α,α-difluoroamines in the presence of Lewis acids with acrylicacid derivatives and subsequent reaction thereof with alkyl hydrazines.

3,5-Bis(fluoroalkyl)pyrazoles are prepared by reacting bisperfluoroalkyldiketones (e.g. 1,1,1,5,5,5-hexafluoroacetylacetone) with hydrazines(cf. Pashkevich et al., Zhurnal Vsesoyuznogo Khimicheskogo Obshchestvaim. D. I. Mendeleeva (1981), 26(1), 105-7), the yield being only 27-40%.The synthesis, isolation and purification of the polyfluoroalkyldiketones is very complex since the compounds are generally veryvolatile and highly toxic.

In the light of the prior art described above, it is an object of thepresent invention to provide a process that does not have theaforementioned disadvantages and hence gives a route to3,5-bis(haloalkyl)pyrazole, especially 3,5-bis(fluoroalkyl)pyrazolederivatives in high yields.

The object described above was achieved by a process for preparing3,5-bis(haloalkyl)pyrazoles of the formula (Ia) and (Ib),

in which

R¹ and R³ are each independently selected from C₁-C₆-haloalkyl;

R² is selected from H, Hal, COOH, (C═O)OR⁴, CN and (C═O)NR⁴R⁵;

R⁴ and R⁵ are each independently selected from C₁₋₁₂-alkyl,C₃₋₈-cycloalkyl, C₆₋₁₈-aryl, C₇₋₁₉-arylalkyl and C₇₋₁₉-alkylaryl

or R⁴ and R⁵ together with the nitrogen atom to which they are bondedmay form a four-, five- or six-membered ring

characterized in that, in step (A), α,α-dihaloamines of the formula(II),

in which

X is independently selected from F, Cl or Br;

R⁵ and R⁶ are each independently selected from C₁₋₁₂-alkyl,C₃₋₈-cycloalkyl, C₆₋₁₈-aryl, C₇₋₁₉-arylalkyl and C₇₋₁₉-alkylaryl

or

R⁵ and R⁶ together with the nitrogen atom to which they are bonded mayform a five- or six-membered ring;

R¹ is as defined above

are reacted with compounds of the formula (III),

in which

R² and R³ are as defined above

to form the compound of formula (IV) or (V)

and that in step (B) in the presence of an acid and hydrazine thecyclization of (IV) or (V) takes place to form (Ia/Ib).

Preferred is a process according to the invention, where the radicals informula (Ia), (Ib), (II), (III), (IV) and (V) are defined as follows:

R¹ and R³ are each independently selected from difluoromethyl,trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl,chlorodifluoromethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, tetrafluoroethyl(CF₃CFH), pentafluoroethyl and 1,1,1-trifluoroprop-2-yl;

R² is selected from H, Cl, Br, COOCH₃, COOC₂H₅, COOC₃H₇, CN andCONMe_(2,) CON (C₂H₅)₂;

X is independently selected from F or Cl.

Furthermore preferred is a process according to the invention, where theradicals in formula (Ia), (Ib), (II), (III), (IV) and (V) are defined asfollows:

R¹ and R³ are each independently selected from difluoromethyl,trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl,chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, tetrafluoroethyl(CF₃CFH), pentafluoroethyl and 1,1,1-trifluoroprop-2-yl;

R² is selected from H, Cl, Br, COOCH₃, COOC₂H₅, COOC₃H₇, CN and CONMe₂,CON (C₂H₅)₂;

X is independently selected from F or Cl;

R⁵ and R⁶ are each independently selected from methyl, ethyl, n-,isopropyl, n-, iso-, sec- and t-butyl, n-pentyl, n-hexyl,1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl, n-nonyl, n-decyl,n-undecyl or n-dodecyl, cyclopropyl, cyclopentyl and cyclohexyl

or

R⁵ and R⁶ together with the nitrogen atom to which they are bonded mayform a five-membered ring.

More preferred is a process according to the invention, where theradicals in formula (Ia), (Ib), (II), (III), (IV) and (V) are defined asfollows are defined as follows:

R¹ and R³ are each independently selected from trifluoromethyl,difluoromethyl, difluorochloromethyl, pentafluoroethyl;

R² is selected from H, Cl, CN, COOC₂H₅;

X is independently F or Cl.

Furthermore more preferred is a process according to the invention,where the radicals in formula (Ia), (Ib), (II), (III), (IV) and (V) aredefined as follows are defined as follows:

R¹ and R³ are each independently selected from trifluoromethyl,difluoromethyl, difluorochloromethyl, pentafluoroethyl;

R² is selected from H, Cl, CN, COOC₂H₅;

X is independently F or Cl;

R⁵ and R⁶ are each independently selected from methyl, ethyl, n-,isopropyl, n-, iso-, sec- and t-butyl, n-pentyl, n-hexyl,1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl, n-nonyl.

Most preferred is a process according to the invention, where theradicals in formula (Ia), (Ib), (II), (III), (IV) and (V) are defined asfollows:

R¹ and R³ are CF₂H;

R² is selected from H

X is F.

Furthermore most preferred is a process according to the invention,where the radicals in formula (Ia), (Ib), (II), (III), (IV) and (V) aredefined as follows:

R¹ and R³ are CF₂H;

R² is selected from H;

X is F;

R⁵ and R⁶ are methyl.

Surprisingly, the pyrazoles of the formula (I) can be prepared under theconditions according to the invention with good yields and in highpurity. That means that the process according to the invention overcomesthe above-mentioned disadvantages of the preparation processespreviously described in the prior art.

General Definitions

In the context of the present invention, the term “halogens” (Hal),unless defined differently, comprises those elements which are selectedfrom the group comprising fluorine, chlorine, bromine and iodine,preferably fluorine, chlorine and bromine, more preferably fluorine andchlorine.

Optionally substituted groups may be mono- or polysubstituted, where thesubstituents in the case of poly substitutions may be the same ordifferent.

Haloalkyl: straight-chain or branched alkyl groups having 1 to 6 andpreferably 1 to 3 carbon atoms (as specified above), where some or allof the hydrogen atoms in these groups may be replaced by halogen atomsas specified above, for example (but not limited to) C₁-C₃-haloalkylsuch as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl,dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl,1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and1,1,1-trifluoroprop-2-yl. This definition also applies to haloalkyl aspart of a composite substituent, for example haloalkylaminoalkyl etc.,unless defined elsewhere. Preference is given to alkyl groupssubstituted by one or more halogen atoms, for example trifluoromethyl(CF₃), difluoromethyl (CHF₂), CF₃CH₂, CF₂Cl or CF₃CCl₂.

Alkyl groups in the context of the present invention, unless defineddifferently, are linear, branched or cyclic saturated hydrocarbylgroups. The definition C₁-C₁₂-alkyl encompasses the widest range definedherein for an alkyl group. Specifically, this definition encompasses,for example, the meanings of methyl, ethyl, n-, isopropyl, n-, iso-,sec- and t-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl,3,3-dimethylbutyl, n-heptyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl.

Alkenyl groups in the context of the present invention, unless defineddifferently, are linear, branched or cyclic hydrocarbyl groupscontaining at least one single unsaturation (double bond). Thedefinition C₂-C₁₂-alkenyl encompasses the widest range defined hereinfor an alkenyl group. Specifically, this definition encompasses, forexample, the meanings of vinyl; allyl (2-propenyl), isopropenyl(1-methylethenyl); but-1-enyl (crotyl), but-2-enyl, but-3-enyl;hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl; hept-1-enyl,hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl;oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl,oct-7-enyl; non-1-enyl, non-2-enyl, non-3-enyl, non-4-enyl, non-5-enyl,non-6-enyl, non-7-enyl, non-8-enyl; dec-1-enyl, dec-2-enyl, dec-3-enyl,dec-4-enyl, dec-5-enyl, dec-6-enyl, dec-7-enyl, dec-8-enyl, dec-9-enyl;undec-1-enyl, undec-2-enyl, undec-3-enyl, undec-4-enyl, undec-5-enyl,undec-6-enyl, undec-7-enyl, undec-8-enyl, undec-9-enyl, undec-10-enyl;dodec-1-enyl, dodec-2-enyl, dodec-3-enyl, dodec-4-enyl, dodec-5-enyl,dodec-6-enyl, dodec-7-enyl, dodec-8-enyl, dodec-9-enyl, dodec-10-enyl,dodec-11-enyl; buta-1,3-dienyl or penta-1,3-dienyl.

Alkynyl groups in the context of the present invention, unless defineddifferently, are linear, branched or cyclic hydrocarbyl groupscontaining at least one double unsaturation (triple bond). Thedefinition C₂-C₁₂-alkynyl encompasses the widest range defined hereinfor an alkynyl group. Specifically, this definition encompasses, forexample, the meanings of ethynyl (acetylenyl); prop-1-ynyl andprop-2-ynyl.

Cycloalkyl: monocyclic, saturated hydrocarbyl groups having 3 to 8 andpreferably 3 to 6 carbon ring members, for example (but not limited to)cyclopropyl, cyclopentyl and cyclohexyl. This definition also applies tocycloalkyl as part of a composite substituent, for examplecycloalkylalkyl etc., unless defined elsewhere.

Aryl groups in the context of the present invention, unless defineddifferently, are aromatic hydrocarbyl groups which may have one, two ormore heteroatoms selected from O, N, P and S. The definition C₆₋₁₈-arylencompasses the widest range defined herein for an aryl group having 5to 18 skeleton atoms, where the carbon atoms may be exchanged forheteroatoms. Specifically, this definition encompasses, for example, themeanings of phenyl, cycloheptatrienyl, cyclooctatetraenyl, naphthyl andanthracenyl; 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl,3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl,4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,4-triazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl and1,3,4-triazol-2-yl; 1 -pyrrolyl, 1-pyrazolyl, 1,2,4-triazol-1-yl,1-imidazolyl, 1,2,3-triazol-1-yl, 1,3,4-triazol-1-yl; 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl and 1,2,4-triazin-3-yl.

Arylalkyl groups (aralkyl groups) in the context of the presentinvention, unless defined differently, are alkyl groups which aresubstituted by aryl groups, may have one C₁₋₈-alkylene chain and mayhave, in the aryl skeleton, one or more heteroatoms selected from O, N,P and S. The definition C₇₋₁₉-aralkyl group encompasses the widest rangedefined herein for an arylalkyl group having a total of 7 to 19 atoms inthe skeleton and alkylene chain Specifically, this definitionencompasses, for example, the meanings of benzyl and phenylethyl.

Alkylaryl groups (alkaryl groups) in the context of the presentinvention, unless defined differently, are aryl groups which aresubstituted by alkyl groups, may have one C₁₋₈-alkylene chain and mayhave, in the aryl skeleton, one or more heteroatoms selected from O, N,P and S. The definition C₇₋₁₉-alkylaryl group encompasses the widestrange defined herein for an alkylaryl group having a total of 7 to 19atoms in the skeleton and alkylene chain Specifically, this definitionencompasses, for example, the meanings of tolyl or 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dimethylphenyl.

The term intermediate used in the context of the present inventiondescribes the substances which occur in the process according to theinvention and are prepared for further chemical processing and areconsumed or used therein in order to be converted to another substance.The intermediates can often be isolated and intermediately stored or areused without prior isolation in the subsequent reaction step. The term“intermediate” also encompasses the generally unstable and short-livedintermediates which occur transiently in multistage reactions (stagedreactions) and to which local minima in the energy profile of thereaction can be assigned.

The inventive compounds may be present as mixtures of any differentisomeric forms possible, especially of stereoisomers, for example E andZ isomers, threo and erythro isomers, and optical isomers, but ifappropriate also of tautomers. Both the E and the Z isomers aredisclosed and claimed, as are the threo and erythro isomers, and alsothe optical isomers, any mixtures of these isomers, and also thepossible tautomeric forms.

PROCESS DESCRIPTION

The process is illustrated in Scheme 1:

Step (A)

In step (A), α,α-dihaloamines of the formula (II) are first reacted inthe presence of a Lewis acid [L] , with compounds of the formula (III).In some cases the reaction also works without a Lewis acid [L].

Preferred compounds of the general formula (II) are1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA),1,1,2,2-tetrafluoroethyl-N,N-diethylamine,1,1,2-trifluoro-2-(trifluoromethyl)ethyl-N,N-dimethylamine,1,1,2-trifluoro-2-(trifluoromethyl)ethyl-N,N-diethylamine (Ishikawa'sreagent), 1,1,2-trifluoro-2-chloroethyl-N,N-dimethylamine and1,1,2-trifluoro-2-chloroethyl-N,N-diethylamine (Yarovenko's reagent).

Compounds of the general formula (II) are used as aminoalkylatingagents. Preference is given to1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA) and1,1,2,2-tetrafluoroethyl-N,N-diethylamine, and particular preference to1,1,2,2-tetrafluoroethyl-N,N-dimethylamine. α,α-Dihaloamines such asTFEDMA and Ishikawa's reagent are commercially available or can beprepared (cf. Yarovenko et al., Zh. Obshch. Khim 1959, 29, 2159, Chem.Abstr. 1960, 54, 9724h or Petrov et al., J. Fluor. Chem. 109, 2001,25-31.

Yagupolskii et al. (Zh. Organicheskoi Khim (1978), 14(12), 2493-6) showsthat the reaction of Yarovenko's reagent (FClCHCF₂NEt₂) with nitriles ofthe formula RCH₂CN (R═CN, CO₂Et) affords the derivatives of the formula(NC)RC═C(NEt₂)CHFCl in approx. 70% yield. Keto compounds of the formula(III) do not react with α,α-dihaloamines of the formula (II) under thiscondition.

Petrov et al. (J. of Fluorine Chem. (2011), 132(12), 1198-1206) showsthat TFEDMA (HCF₂CF₂NMe₂) reacts with cyclic β-diketones to transfer adifluoroacetyl group.

In a preferred embodiment the α,α-dihaloamine are first reacted withLewis acid [L], for example BF₃, AlCl₃, SbCl₅, SbF₅, ZnCl₂, and thencompound of the formula (III) is added in substance or dissolved in asuitable solvent (cf. WO 2008/022777).

α,α-Dihaloamines are reacted with Lewis acids [L] (preparation of theiminium salts of the formula (VIII) according to the teaching of WO2008/022777). According to the invention, the reaction is effected attemperatures of −20° C. to +40° C., preferably at temperatures of −20 °C. to +30 ° C., more preferably at −10 to 20° C. and under standardpressure. Due to the hydrolysis sensitivity of the α,α-dihaloamines, thereaction is conducted in an anhydrous apparatus under inert gasatmosphere.

The reaction time is not critical and may, according to the batch sizeand temperature, be selected within a range between a few minutes andseveral hours.

According to the invention, 1 mol of the Lewis acid [L] is reacted withequimolar amounts of the α,α-dihaloamine of the formula (II).

For the process according to the invention 1,8 to 4, preferably 2 to 3mol of the compound of the formula (II) is reacted with 1 mol of azineof the formula (III).

Preference is given to using compounds of the formula (III) selectedfrom the group comprising—bis(1,1,1-trifluoropropan-2-ylidene)hydrazine,bis(1,1-difluor-1-chlorpropan-2-ylidene)hydrazine,bis(1,1-difluoropropan-2-ylidene)hydrazine.

Suitable solvents are, for example, aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether, n-hexane, n-heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, andhalogenated hydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane, ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such asacetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile;amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide;sulphoxides such as dimethyl sulphoxide or sulphones such as sulpholane.Particular preference is given, for example, to THF, acetonitriles,ethers, toluene, xylene, chlorobenzene, n-hexane, cyclohexane ormethylcyclohexane, and very particular preference, for example, toacetonitrile, THF, ether or dichloromethane.

The intermediates of the formula (1V) and (V) formed in step A(Scheme 1) can be used in the cyclization step B (Scheme 1) withoutprior workup.

Alternatively, the intermediates can be isolated and characterized bysuitable workup steps and optionally further purification.

Compounds of formula (III) can be prepared according to a proceduredescribed in J. Org. Chem. 1972, 37, 1314-1316:

Compounds of formula (VI) which are commercially available are reactedwith hydrazine hydrate in the presence of a Lewis Acid, preferably BF₃and AlC₃, and a solvent to form compounds of formula (III). The reactiontemperature is −10° C. to +60° C., preferably 0° C. to 50° C. As solventcan be used alcohols and ethers, preferably ethanol The ratio ofcompound of formula (VI) and hydrazine hydrate is 10:1 to 2:1,preferably 5:1 to 2:1 and more preferably 3:1 to 2:1.

Step (B)

The cyclization in step (B) by reaction of compound (IV) or (V) underacidic conditions with hydrazine in the process according to theinvention is effected at temperatures of 0° C. to +80° C., preferably attemperatures of +20° C. to +60° C., more preferably at +40-50° C. andunder standard pressure.

The reaction time is not critical and may, according to the batch size,be selected within a relatively wide range.

Typically, the cyclization step (B) is effected without changing thesolvent. Typically the cyclization of compound of the formula (IV) or(V) proceeds under acidic condition.

Preference is given to mineral acids, for example H₂SO₄, HCl, HSO₃Cl,HF, HBr, HI, H₃PO₄ or organic acids, for example CF₃COOH,p-toluenesulphonic acid, methanesulphonic acid,trifluoromethanesulphonic acid.

According to the invention, 0.1 mol to 2 mol, preferably 0.1 to 1.5 molof the acid for 1 mol of the compound of formula (IV) or (V) is used.According to the invention, the reaction is effected at temperatures of−20° C. to +80° C., preferably at temperatures of −10° C. to +60° C.,more preferably at +10° C. to 50° C. and under standard pressure. Thereaction time is not critical and may, according to the batch size andtemperature, be selected within a range between a few minutes andseveral hours. In most cases it is enough to add just a water to thereaction mixture after step 1 to achieve low pH due the formation ofacid (HF) during the step 1.

According to the invention, 1 mol to 2 mol, preferably 1 to 1.5 mol ofthe hydrazine for 1 mol of the compound of formula (IV) or (V) is used.Hydrazine could be used in the form of its salt like hydrazinehydrochloride or sulphate. According to the invention, the cyclizationis effected at temperatures of −20° C. to +80° C., preferably attemperatures of −10° C. to +60° C., more preferably at +20° C. to 50° C.and under standard pressure. The reaction time is not critical and may,according to the batch size and temperature, be selected within a rangebetween a few minutes and several hours.

Suitable solvents are, for example, aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether, n-hexane, n-heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, andhalogenated hydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane, ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; alcohols such asmethanol, ethanol, isopropanol or butanol, nitriles such asacetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile;amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide;sulphoxides such as dimethyl sulphoxide or sulphones such as sulpholane.Particular preference is given, for example, to acetonitrilestoluene,xylene, chlorobenzene, n-hexane, cyclohexane or methylcyclohexane, andvery particular preference, for example, to acetonitriles, THF, tolueneor xylene. After the reaction has ended, for example, the solvents areremoved and the product is isolated by filtration, or the product isfirst washed with water and extracted, the organic phase is removed andthe solvent is removed under reduced pressure.

The compounds of the formula (I) where R² equals COOR⁴ can then beconverted to pyrazole acids of the formula (I) R² equals COOH.

The conversion is generally performed under acidic or basic conditions.

For acidic hydrolysis, preference is given to mineral acids, for exampleH₂SO₄, HCl, HSO₃Cl, HF, HBr, HI, H₃PO₄ or organic acids, for exampleCF₃COOH, p-toluenesulphonic acid, methanesulphonic acid,trifluoromethanesulphonic acid. The reaction can be accelerated by theaddition of catalysts, for example FeCl₃, AlCl₃, BF₃, SbCl₃, NaH₂PO₄ .The reaction can likewise be performed without addition of acid, only inwater.

Basic hydrolysis is effected in the presence of inorganic bases such asalkali metal hydroxides, for example lithium hydroxide, sodium hydroxideor potassium hydroxide, alkali metal carbonates, for example Na₂CO₃,K₂CO₃ and alkali metal acetates, for example NaOAc, KOAc, LiOAc, andalkali metal alkoxides, for example NaOMe, NaOEt, NaOt-Bu, KOt-Bu oforganic bases such as trialkylamines, alkylpyridines, phosphazenes and1,8-diazabicyclo[5.4.0]undecene (DBU). Preference is given to theinorganic bases, for example NaOH, KOH, Na₂CO₃ or K₂CO_(3.)

Preference is given to conversion by means of basic hydrolysis.

The process step of the invention is performed preferably within atemperature range from 20° C. to +150° C., more preferably attemperatures of 30° C. to +110° C., most preferably at 30° C. to 80° C.

The process step of the invention is generally performed under standardpressure. Alternatively, however, it is also possible to work undervacuum or under elevated pressure (for example reaction in an autoclavewith aqueous HCl).

The reaction time may, according to the batch size and the temperature,be selected within a range between 1 hour and several hours.

The reaction step can be performed in substance or in a solvent.Preference is given to performing the reaction in a solvent. Suitablesolvents are, for example, selected from the group comprising water,alcohols such as methanol, ethanol, isopropanol or butanol, aliphaticand aromatic hydrocarbons, for example n-hexane, benzene or toluene,which may be substituted by fluorine and chlorine atoms, such asmethylene chloride, dichloroethane, chlorobenzene or dichlorobenzene;ethers, for example diethyl ether, diphenyl ether, methyl tert-butylether, isopropyl ethyl ether, dioxane, diglyme, dimethylglycol,dimethoxyethane (DME) or THF; nitriles such as methyl nitrile, butylnitrile or phenyl nitrile; amides we dimethylformamide (DMF) orN-methylpyrrolidone (NMP) or mixtures of such solvents, particularpreference being given to water, acetonitrile, dichloromethane andalcohols (ethanol).

The inventive compounds (Ia) and (Ib) are used for preparation of activefungicidal ingredients.

EXAMPLE 1 Bis(1,1-difluoropropan-2-ylidene) hydrazine (III-1).

To a stirred solution of difluoroacetone (32 g, 0.342 mmol) in 300 mlmethyl-tert butyl ether hydrazine hydrate (8.6 g., 0.171 mmol) was addedat 0° C. After stirring at room temperature for 1 h the addition productwas observed in ¹⁹F-NMR showing two diastereomeres. 0.1 ml ofBF₃-etherate was added. The mixture was stirred under reflux for 40 min.After drying over Na₂SO₄ all volatiles were removed and the residue wasdistilled at 125° C. to 127° C. to give the desired productbis(1,1-difluoropropan-2-ylidene) hydrazine (III-1) as yellow liquid.

Yield: 23 g, 125 mmol, 73%.

EXAMPLE 2 Bis(1,1,1-trifluoropropan-2-ylidene)hydrazine (III-2)

is prepared analogously to the compound of example 1 fromtrifluoroacetone.b.p.: 58-60° C./180 mbar.

EXAMPLE 3 3,5-bis(difluoromethyl)-1H-pyrazole (I-1)

To a solution of TFEDMA (4.35 g, 30 mmol) in 20 mL CH₃CN under Argon ina Teflon flask BF₃(OEt₂) (4.25 g, 30 mmol) was added at 10° C. Thesolution was stirred for 15 min at room temperature and a solution of(1.84 g., 10 mmol) of bis(1,1-difluoropropan-2-ylidene) hydrazine in 5ml CH₃CN was added and the mixture was stirred at the room temperaturefor 18 h. After 18 h (1.5 g, 22 mmol) of hydrazin hydrochloride and 5 mlwater were added to the reaction mixture. The mixture was stirred for 4h at 40° C. and the solvent was removed in vacuo at 30° C. The residuewas dissolved in 50 ml methyl-tert.butylether and washed 3 times withwater. After solvent removal the oil product which slowly solidified wasobtained. For further purification the crude product could be destilledin vacuo or purified by column chromatography on silica gel withpentane/diethyl ether (100:0 to 60:40) as eluent to afford the puretitle compound (2.72 g, 81%) as a pale yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 12.5 (br, 1H), 6.77 (t, 2H, J=54.8 Hz), 6.74(s, 1H); ¹³C (101 MHz, CDCl₃) δ 142.9, 109.3 (t, J_(C−F)=236 Hz), 103.2;¹⁹F (376 MHz, CDCl₃) δ −113.2 (d, 4F, J=54.4 Hz); HRMS (ESI) calc. forC₅H₅F₄N₂ [M+H]⁺ 169.039, found 169.038

1. A process for preparing a 3,5-bis(haloalkyl)pyrazole of formula (Ia)and (Ib)

in which R¹ and R³ are each independently selected from C₁-C₆-haloalkyl;_(R) ² is selected from H, Hal, COOH, (C═O)OR⁴, CN and (C═O)NR⁴R⁵; R⁴and R⁵ are each independently selected from C₁₋₁₂-alkyl,C₃₋₈-cycloalkyl, C₆₋₁₈-aryl, C₇₋₁₉-arylalkyl and C₇₋₁₉-alkylaryl, or R⁴and R⁵ together with the nitrogen atom to which they are bonded may forma four-, five- or six-membered ring; comprising in (A), reacting one ormore α,α-dihaloamines of the formula (II),

in which X is independently selected from F, Cl or Br; R⁵ and R⁶ areeach independently selected from C₁₋₁₂-alkyl, C₃₋₈-cycloalkyl,C₆₋₁₈-aryl, C₇₋₁₉-arylalkyl and C₇₋₁₉-alkylaryl or where R⁵ and R⁶together with the nitrogen atom to which they are bonded may form afive- or six-membered ring; R¹ is as defined above; with one or morecompounds of formula (III),

in which R² and R³ are as defined above; to form the compound of formula(IV) or (V)

And in (B) in the presence of an acid and hydrazine cyclization of (IV)or (V) takes place to form (Ia/Ib).
 2. A process according to claim 1,wherein R¹ and R³ are each independently selected from trifluoromethyl,difluoromethyl, difluorochloromethyl, pentafluoroethyl; R² is selectedfrom H, Cl, CN, COOC₂H₅; X is independently F or Cl.
 3. A processaccording to claim 1, wherein R¹ and R³ are each independently selectedfrom trifluoromethyl, difluoromethyl, difluorochloromethyl,pentafluoroethyl; R² is selected from H, Cl, CN, COOC₂H₅; X isindependently F or Cl; R⁵ and R⁶ are each independently selected frommethyl, ethyl, n-, isopropyl, n-, iso-, sec- and t-butyl, n-pentyl,n-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl, n-nonyl.
 4. Aprocess according to claim 1, wherein R¹ and R³ are CF₂H; R² is selectedfrom H X is F.
 5. A process according to claim 1, wherein R¹ and R³ areCF₂H; R² is selected from H; X is F; R⁵ and R⁶ are methyl.
 6. A processaccording to claim 1 wherein the compound of formula (II) is1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA),1,1,2,2-tetrafluoroethyl-N,N-diethylamine,1,1,2-trifluoro-2-(trifluoromethyl)ethyl-N,N-dimethylamine,1,1,2-trifluoro-2-(trifluoromethyl)-ethyl-N,N-diethylamine,1,1,2-trifluoro-2-chloroethyl-N,N-dimethylamine or1,1,2-trifluoro-2-chloroethyl-N,N-diethylamine.
 7. A compound of formula(III-1): Bis(1,1-difluoropropan-2-ylidene) hydrazine


8. A process for preparing Bis(1,1-difluoropropan-2-ylidene) hydrazineof formula (III-1)

wherein, one or more ketones of formula (VI),

in which R³ is selected from C₁-C₆-haloalkyl; R² is selected from H,Hal, COOH, (C═O)OR⁴, CN and (C═O)NR⁴R⁵; R² and R³ are reacted withhydrazine hydrate in the presence of a Lewis Acid, optionally BF₃ orAlCl₃ and a solvent R⁴ and R⁵ are each independently selected fromC₁₋₁₂-alkyl, C₃₋₈-cycloalkyl, C₆₋₁₈-aryl, C₇₋₁₉-arylalkyl andC₇₋₁₉-alkylaryl, or R⁴ and R⁵ together with the nitrogen atom to whichthey are bonded may form a four-, five- or six-membered ring.